PROJECT SUMMARY Immune checkpoint blockade has proven an effective treatment for a subset of head and neck cancer (HNC) patients. However, over 85% of the patients cannot benefit from this strategy, largely due to the highly immunosuppressive tumor microenvironment (TME) in established cancers. Oral leukoplakias / Oral Epithelial Dysplasias (OEDs) precede HNC and offer a unique time window for disease eradication. However, surgical resection in the orofacial region results in significant morbidity and function loss, and more importantly, cannot reverse field cancerization. A subset of OEDs transform into malignancy despite vigilant follow-ups. Frequent immune cell infiltration is a common feature of OEDs, however, little is known about when and how OEDs evade from immuno-surveillance and reach a point-of-no-return. In addition, it remains unclear which sub- group of OEDs is more likely to suppress host immunity and establish themselves as high-risk lesions. Amplification of the chromosome locus 3q26.3 is a defining genomic feature of HNC, and two oncogenes at this locus inhibit innate immune sensing pathways and elicit a metabolic restraint in the TME, which collectively disadvantage anti-tumor immune cells. We have developed strategies to bypass the inhibition of innate immune sensing and synthesized a novel drug-like molecule that exhibits potent metabolic remodeling potential and anti-tumor activity in vivo. We constructed two unique genetically engineered mouse models, which can model a spectrum of OED/HNC lesions with high-fidelity histologic and immunophenotypic resemblance to human diseases, to recapitulate 3q26.3-driven OED transformation. We also identified unique collections of case-control and longitudinal paired OED/HNC specimens, which allow us to validate key findings on the temporal shift of exploitable immune targets with clinical specimens. The overarching goal of this translational program is to test the hypothesis that 3q26.3 amplification is a key early high-risk event that leads to OED immune escape and that a combination of metabolic remodeling agent with immunotherapy effectively prevents OED progression. Thus, this proposal is fully responsive to the RFA-CA-19-014 and is focused on the deeper understanding of the time-course of immune landscape shift as pre-malignant lesions progress, using 3q26.3 amplification-driven OEDs as a high-risk disease model. We will qualify a novel metabolic remodeling drug-like molecule as a priming agent to maximally improve immuno-prevention. The 3q26.3 amplification is not unique to HNC and commonly found in squamous cell carcinomas of the lung, esophagus and skin, hence, our findings will help address a broad class of public health concerns.